NORTHERA (DROXIDOPA) for Dysautonomia in Adult Survivors of Menkes Disease and Occipital Horn Syndrome

Phase I/II Study of NORTHERA (DROXIDOPA) for Dysautonomia in Adult Survivors of Menkes Disease and Adults With Occipital Horn Syndrome: Double-blind Placebo-controlled Randomized Crossover Clinical Trial

The purpose of this study is to evaluate whether Northera (Droxidopa) is safe and effective in young adults with Menkes disease who survived the most severe complications of their illness or adults with occipital horn syndrome (OHS), who have trouble with intermittent low blood pressure and other symptoms of dysautonomia. The outcomes and information from this study may help adult survivors of Menkes disease and individuals with OHS lead more normal day-to-day lives.

Study Overview

• Status: Completed
• Conditions: Menkes Disease; Occipital Horn Syndrome
• Intervention / Treatment: Drug: Droxidopa; Other: Placebo

Detailed Description

This pilot clinical trial will evaluate the safety, tolerability, dosing, and preliminary efficacy of Northera (Droxidopa) treatment in young adults who survived the major neurodegenerative and neurocognitive effects of Menkes disease through early Copper Histidinate treatment. We hypothesize that Northera (Droxidopa) in Menkes disease survivors with symptoms of dysautonomia (e.g., syncope, dizziness, orthostatic hypotension, abnormal sinoatrial conduction, nocturnal bradycardia, and bowel or bladder dysfunction) from persistent deficiency of the copper-dependent enzyme, dopamine-β-hydroxylase, will be safe, and correct or improve blood neurochemical levels, raise systolic blood pressure, and produce symptomatic improvement and better overall quality of life. We will test this hypothesis in six to ten Menkes disease survivors or OHS patients in a double-blind placebo-controlled randomized crossover clinical trial.

• Study Type: Interventional
• Enrollment (Actual): 3
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10032
      • Vagelos College of Physicians and Surgeons, Columbia University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Adult persons with Menkes disease who survived beyond the expected natural history, attained independent ambulation, attend (or attended) school, and reached adulthood after early CuHis treatment for three years or adults with Occipital Horn Syndrome, who manifest clinical signs and symptoms of dysautonomia, e.g., orthostatic hypotension: specifically, a decrease in systolic or diastolic blood pressure of at least 20 or 10 mm Hg, respectively, within three minutes after standing, and/or chronic diarrhea: production of loose stools with or without increased stool frequency for more than four weeks immediately preceding enrollment.
2. History of at least thrice weekly occurrence of dizziness/feeling lightheaded while standing upright and/or thrice weekly episodes of diarrhea or an urgent need to defecate after food ingestion for more than four weeks immediately preceding enrollment.
3. Documented mutation in ATP7A.
4. Must sign and date an Informed Consent Form (ICF).
5. Age ≥ 18 years of age.
6. Ability to adhere to the prescribed oral Northera (Droxidopa) regimen.
7. Willingness to comply with all study visits and procedures.

Exclusion Criteria:

1. Pre-existing liver (e.g., hepatitis, biliary atresia, cirrhosis) or kidney disease (i.e., calculated glomerular filtration rate <30 ml/min).
2. History of hypertension, anti-hypertensive therapy, heart failure (or decreased ejection fraction), cardiac arrhythmia, or bleeding diatheses.
3. Any disease or condition that, in the opinion of the Investigator, has a high probability of precluding the subject from completing the study or where the subject cannot or will not appropriately comply with study requirements.
4. Any alpha-1 adrenoreceptor agonist, beta-blocker, DOPA decarboxylase inhibitor, midodrine, ephedrine, or any triptan medication as a concomitant medication.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Northera™ (Droxidopa) (Treatment A); Northera (Droxidopa) (Treatment A) will be provided to adult subjects as a capsule with 100mg, 200mg, or 300mg of Northera (Droxidopa) contained within gelatin color capsules (sky blue and white, size 0) based on findings from the dose titration visit. These capsules are physically indistinguishable from the Treatment B (placebo) capsules. Frequency of administration (by mouth) will be twice daily for six weeks.	Drug: Droxidopa; Subjects will self-administer capsules of Droxidopa by mouth twice daily for six weeks.; Other Names: Northera
Placebo Comparator: Placebo (Treatment B); Empty gelatin color capsules (sky blue and white, size 0) filled with cellulose microcrystalline and physically indistinguishable from Treatment A capsules. Frequency of administration (by mouth) will be twice daily for six weeks	Other: Placebo; Subjects will self-administer capsules of placebo by mouth twice daily for six weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment Related Adverse Events as Assessed by CTCAE v4.0	Treatment related adverse events as assessed by CTCAE v 4.0 by study arm	TEAEs in 6 week periods of either active drug (droxidopa) or placebo

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Change in Systolic Blood Pressure in Tilt Position	Change in systolic BP in tilt position during each treatment arm (droxidopa and placebo) compared to baseline.	Change in systolic BP in tilt position during each 6 week treatment arm (droxidopa and placebo) compared to baseline.
Mean Change in Diastolic Blood Pressure in Tilt Position	The change in diastolic BP in tilt position during each treatment arm (droxidopa and placebo) compared to baseline.	The change in diastolic BP in tilt position during each 6 week treatment arm (droxidopa and placebo) compared to baseline.
Plasma Catechol Levels	Change in plasma catechols between placebo and droxidopa treatment arms	Change in plasma catechols between each 6 week treatment arm (droxidopa and placebo)
Change From Baseline in Daily Bowel Movements	Change from baseline in daily bowel movements	Change from baseline in daily bowel movements per day during each 6 week treatment arm (droxidopa and placebo).
Change From Baseline in Time Standing Duration	Change from baseline in Time standing duration	Change from baseline in standing time duration during each 6 week treatment arm (droxidopa and placebo).
Change From Baseline in Timed Up and Go (TUG) Test Performance	Change from baseline in Timed Up and Go (TUG) test performance	Change from baseline in TUG test performance during each 6 week treatment arm (droxidopa and placebo)
Change From Baseline in 6 Minute Walk Test Performance	Change from baseline in 6 minute walk test performance	Change from baseline in the 6MW distance during each 6 week treatment arm (droxidopa and placebo)
Change From Baseline in Scores on the Orthostatic Hypotension Symptom Assessment (OHSA) Questionnaire	Change from baseline in scores on the Orthostatic Hypotension Symptom Assessment questionnaire. The scale rates the severity of OH symptoms from 0 to 10 ; with 10 defined as the worst possible.	Change from baseline in OHSA score during each 6 week treatment arm (droxidopa and placebo)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in scores on the Orthostatic Hypotension Symptom Assessment questionnaire after Northera (Droxidopa)	Scores range from zero to 10 with 0 meaning no symptoms and 10 meaning the worst possible symptoms	Six week periods of active drug versus placebo

Collaborators and Investigators

• Sponsor: Stephen G. Kaler, MD
• Investigators: Principal Investigator: Stephen G Kaler, MD, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY

Study record dates

Study Major Dates

• Study Start (Actual): July 12, 2021
• Primary Completion (Actual): October 30, 2023
• Study Completion (Actual): June 29, 2024

Study Registration Dates

• First Submitted: July 9, 2021
• First Submitted That Met QC Criteria: July 22, 2021
• First Posted (Actual): July 26, 2021

Study Record Updates

• Last Update Posted (Actual): April 13, 2026
• Last Update Submitted That Met QC Criteria: March 23, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Dysautonomia
• Additional Relevant MeSH Terms: Neurologic Manifestations; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases; Neurobehavioral Manifestations; Skin Diseases; Hair Diseases; Heredodegenerative Disorders, Nervous System; Intellectual Disability; Genetic Diseases, X-Linked; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Metal Metabolism, Inborn Errors; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Nutritional and Metabolic Diseases; Skin and Connective Tissue Diseases; X-Linked Intellectual Disability; Autonomic Nervous System Diseases; Menkes Kinky Hair Syndrome; Occipital horn syndrome; Amino Acids, Peptides, and Proteins; Organic Chemicals; Hydrocarbons; Hydrocarbons, Cyclic; Hydrocarbons, Aromatic; Amines; Amino Acids; Catechols; Phenols; Benzene Derivatives; Catecholamines; Norepinephrine; Serine; Amino Acids, Neutral; Droxidopa
• Other Study ID Numbers: 00001113

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No